Chang Katherine, Svabek Catherine, Vazquez-Guillamet Cristina, Sato Bryan, Rasche David, Wilson Strother, Robbins Paul, Ulbrandt Nancy, Suzich JoAnn, Green Jonathan, Patera Andriani C, Blair Wade, Krishnan Subramaniam, Hotchkiss Richard
Crit Care. 2014 Jan 4;18(1):R3. doi: 10.1186/cc13176.
A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.
Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry.
Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).
In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.
脓毒症的一个主要病理生理机制是宿主免疫受损，这导致无法根除入侵病原体，并增加了继发感染的易感性。尽管存在许多免疫抑制机制，但抑制性受体程序性细胞死亡1（PD-1）及其配体（PD-L1）的表达增加被认为起着关键作用。新认识的T细胞耗竭现象部分由PD-1对T细胞的作用介导。本研究测试了抗PD-1和抗PD-L1抗体预防脓毒症患者细胞凋亡和改善淋巴细胞功能的能力。
从43例脓毒症患者和15例非脓毒症重症患者获取血液。通过流式细胞术定量抗PD-1、抗PD-L1或同型对照抗体对淋巴细胞凋亡以及干扰素γ（IFN-γ）和白细胞介素-2（IL-2）产生的影响。
与非脓毒症患者相比，脓毒症患者的淋巴细胞产生的IFN-γ和IL-2减少，CD8 T细胞的PD-1表达增加，PD-L1表达降低（P<0.05）。与非脓毒症患者相比，脓毒症患者的单核细胞PD-L1增加，HLA-DR表达降低（P<0.01）。在重症监护病房（ICU）中，随着PD-L1、IFN-γ和IL-2的降低，CD8 T细胞的PD-1表达随时间增加。此外，CD8 PD-1表达最高且CD8 PD-L1表达最低的供体，其单核细胞中的HLA-DR表达水平也较低，继发感染率增加，提示免疫耗竭表型更明显。用抗PD-1或抗PD-L1抗体处理脓毒症患者的细胞可减少细胞凋亡，并增加脓毒症患者的IFN-γ和IL-2产生；（P<0.01）。PD-1阳性的CD4 T细胞百分比与细胞凋亡程度相关（P<0.01）。
体外阻断PD-1:PD-L1途径可减少脓毒症患者的细胞凋亡并改善免疫细胞功能。目前的结果，连同抗PD-1和抗PD-L1在细菌和真菌感染动物模型中的多项阳性研究，以及迄今为止抗PD-1/抗PD-L1在人类肿瘤试验中的相对安全性，有力地支持启动在脓毒症（一种高死亡率疾病）中测试这些抗体的临床试验。
